Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.
Harish N VasudevanEmily PayneCyrille L DelleySiyuan John LiuKanish MirchiaMatthew J SaleSydney LastellaMaria Sacconi NunezCalixto-Hope G LucasCharlotte D EatonTim Casey-ClydeStephen T MagillWilliam C ChenSteve E BraunsteinArie PerryLine JacquesAlyssa T ReddyMelike PekmezciAdam R AbateFrank McCormickDavid R RaleighPublished in: Nature communications (2024)
Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.
Keyphrases
- single cell
- signaling pathway
- lps induced
- pi k akt
- nuclear factor
- rna seq
- oxidative stress
- dna methylation
- inflammatory response
- peripheral nerve
- high throughput
- endothelial cells
- cell proliferation
- gene expression
- public health
- squamous cell carcinoma
- immune response
- machine learning
- mesenchymal stem cells
- data analysis
- smoking cessation